A major challenge to breast cancer research is the identification of alterations in the architecture and composition of the breast that are associated with breast cancer progression. Compositionally, adipose tissue is the major contributor to the volume of the breast. Two types of adipose tissue can be distinguished histologically and functionally: unilocular, white adipose tissue (WAT) which stores excess energy and multilocular brown adipose tissue (BAT), which specializes in the production of heat, In humans, BAT is present at birth and was thought to involute rapidly postnatally. However, positron emission tomography has provided evidence that adults retain metabolically active BAT depots in WAT that can be induced in response to cold and sympathetic nervous system activation. Indeed, BAT has characteristics that are favorable for tumor growth, including high vascularity and the ability to synthesize and secrete angiogenic and growth factors. Yet it is unclear whether the plasticity of adipose tissue (i.e. activation of BAT in traditional WAT depots) can impact breast cancer development. The goal of this proposal is to demonstrate the utility of a preclinical mouse model of Brca1-related breast cancer to provide novel information on how changes in adipose tissue biology can be an important determinant in the development of breast cancer, particularly for those who are genetically at risk. We hypothesize that (1) the persistence of a brown adipocyte-like phenotype in mammary glands with loss of Brca1 contributes to the development of preneoplasia and mammary tumor development; and (2) the mechanism by which the brown adipocyte-like phenotype persists in Brca1 mutant mice may be due, in part, to abnormal estrogen signaling. To test our hypotheses, we will (1) determine if the persistence of brown adipocyte-like cells in mammary glands with loss of Brca1 can increase the incidence of mammary preneoplasia and/or tumor development; and (2) determine whether chronic estrogen signaling in Brca1 mutant mice leads to the persistence of brown adipocyte-like cells in the mammary gland. The potential impact of this research will be the identification of alterations in mammary adipose tissue that are associated with the development of breast cancer that could yield new targets for prevention of this disease. PUBLIC HEALTH RELEVANCE: Breast cancer is the most common malignancy in women worldwide. Early detection can significantly improve the treatment and survival rate of patients with breast cancer. This proposal examines a novel paradigm of tumor development, namely whether a sustained multilocular, brown adipocyte phenotype in mammary adipose can contribute to the progression of breast cancer and be used as an early biomarker for disease. The results of these studies may lead to new therapeutic strategies that can reduce incidence and/or mortality of breast cancer, particularly for women in high risk groups.